Mitochondrial uncoupling is a process that decouples mitochondrial oxidation from ATP synthesis. It is mediated by proton influx across the mitochondrial inner membrane without passing through ATP synthase. Mitochondrial uncoupling occurs naturally in mammals, induced by mitochondrial uncoupler proteins, or UCPs. There are two major types of UCPs, UCP1 and other UCPs such as UCP2 and UCP3. UCP1 is primarily expressed in brown fat tissue (BAT), activation of which leads to rapidly conversion of fat calories (chemical energy) to heat for keeping body temperature. UCP2 is ubiquitously expressed in tissues including liver, brain, heart, and muscles. UCP2 activation leads to a mild mitochondrial uncoupling with limited impact on mitochondrial membrane potential. UCP2 activation increases glucose and lipid metabolism, dissipates fat accumulation, and decreases mitochondrial ROS production. UCP2 activation is a natural response to cellular ROS elevation. Mitochondrial uncoupling thus provides effective means for burning excess fat calories, for consuming cellular metabolites otherwise used for cell proliferation, and for cell protection against oxidative stress.
Mitochondrial uncoupling can be induced by small-molecule mitochondrial uncouplers, which we named miunins. The above figure illustrates mechanistically the processes of oxidative phosphorylation and mitochondrial uncoupling induced by small-molecule miunins. Note in red-dotted box: miunins are lipophilic weak acids functioning within the mitochondrial inner membrane. They exist between the de-protonated form (U–) and protonated form (UH). Near the outer side of the membrane where proton concentration is high, Miunins are protonated. The protonated miunins move to the matrix side by random movements, where they are deprotonated. The protons are then released to the mitochondrial matrix, where the proton concentration is low. As a result, the energy derived from oxidation of fat (or other nutrients) is directly converted to heat rather than for ATP synthesis.
Mito BioPharma has proprietary know-how and platform for development of miunins for therapeutic applications. We have successfully developed miunins that mimic the physiological effects and functions of UCP1 and UCP2/3, which we named Type 2 miunins and Type 3 miunins, respectively (we named the conventional small-molecule mitochondrial uncouplers that completely dissipate mitochondrial membrane potential (MMP) as Type 1 miunins). Extensive proof-of-concept studies have been performed in various animal models demonstrating the efficacy of mitochondrial uncoupling by various miunins on type 2 diabetes, NASH, and cancer, some of which have been published in leading biomedical journals including Nature Medicine. Patent- protected Mito BioPharma miunin pipelines have been developed for treating a variety of diseases including type 2 diabetes (dissipating hepatic fat accumulation and reducing hepatic insulin resistance), NASH (dissipating hepatic fat accumulation, sensitizing hepatic insulin resistance, reducing liver damage, preventing and reversing inflammation and fibrosis, inhibiting hepatic stellate cell activation), hypercholesterolemia (reducing acetyl-CoA supply for cholesterol synthesis in liver), liver cancer, hepatic metastases from other types of cancers, and leukemia (consuming cellular metabolites essential for cell proliferation in cancer cells).